Arabidopsis thaliana plants with null mutations in the genes encoding the a and b subunits of the single heterotrimeric G protein are less and more sensitive, respectively, to O 3 damage than wild-type Columbia-0 plants. The first peak of the bimodal oxidative burst elicited by O 3 in wild-type plants is almost entirely missing in both mutants. The late peak is normal in plants lacking the Gb protein but missing in plants lacking the Ga protein. Endogenous reactive oxygen species (ROS) are first detectable in chloroplasts of leaf epidermal guard cells. ROS production in adjacent cells is triggered by extracellular ROS signals produced by guard cell membrane-associated NADPH oxidases encoded by the AtrbohD and AtrbohF genes. The late, tissue damage-associated component of the oxidative burst requires only the Ga protein and arises from multiple cellular sources. The early component of the oxidative burst, arising primarily from chloroplasts, requires signaling through the heterotrimer (or the Gbg complex) and is separable from Ga-mediated activation of membrane-bound NADPH oxidases necessary for both intercellular signaling and cell death.
These data suggest that Nox1 plays an important role in TLR2-mediated intracellular H2O2 generation, activation of matrix metalloprotease 2, and secretion of pro-inflammatory cytokines, which in turn stimulate MASMC migration and vascular remodelling.
Mucin hypersecretion is an important clinical feature of several respiratory diseases, including asthma, cystic fibrosis, nasal allergy, rhinitis, and sinusitis. It has been shown that a-melanocyte-stimulating hormone (a-MSH), a proopiomelanocortin (POMC)-derived peptide, has immunomodulatory activities by inhibiting NF-kB activation induced by proinflammatory cytokines such as TNF-a. Because MUC5AC expression is known to be up-regulated by TNF-a via NF-kB activation, we evaluated the inhibitory effect of a-MSH on MUC5AC gene expression induced by TNF-a in normal human nasal epithelial (NHNE) cells. Melanocortin-1-receptor (MC-1R) was detected by RT-PCR, Western blotting, and immunofluorescent labeling in NHNE cells. a-MSH suppressed NF-kB/p65 phosphorylation induced by TNF-a as well as IkB-a degradation in a dosedependent manner, as assessed by Western blotting. In addition, a-MSH inhibited TNF-a-induced nuclear translocation of NF-kB and NF-kB luciferase activity. Real-time quantitative PCR data showed that a-MSH inhibited TNF-a-induced expression of MUC5AC, and this effect of a-MSH was neutralized by knockdown of MC-1R using MC-1R shRNA lentivirus. Analyses using RT-PCR and Western blotting showed the expression of POMC and two key enzymes in the POMC processing, proprotein convertases (PC)1 and PC2, and 7B2, which is required for enzymatic activity of PC2, in normal human nasal mucosa. We conclude that a-MSH downregulates MUC5AC expression by inhibiting TNF-a-induced NF-kB activity through MC-1R stimulation in NHNE cells and that normal human nasal mucosa possesses the POMC processing machinery. Therefore, a-MSH may be a promising candidate to decrease mucin overproduction initiated by NF-kB activation.
Vitamin A deficiency (VAD) alters the phenotype of airway epithelium and attenuates the epithelial defense system, and many studies have reported the association of VAD with respiratory disease. In this study, we investigated changes in submucosal glands (SMG) in a mouse model of VAD. C57BL/6 mice were fed a vitamin A-devoid diet and the others were fed a control diet (1.2 mg retinol/kg). The areas of serous and mucous cells of SMG were measured in 4-, 8-, and 20-wk-old male mice. The volume and lysozyme concentration of glandular secretions were also measured. The 2 groups did not differ in body weight or general morbidity at 3-10 wk of age, although serum retinol concentrations were greater in the control mice than in the VAD mice after 4 wk. Upon histological evaluation, we found that the areal ratio of serous cells:total SMG cells was significantly lower after 8 wk in the VAD mice compared with the control mice, although the total area of SMG did not differ between groups throughout the 20-wk experiment. The number of secretory bubbles did not differ between the groups, but total secretion volume was reduced by 35% in 8-wk-old VAD mice compared with controls. Furthermore, the concentration of lysozyme in secretions from 8-wk-old VAD mice was also less than in controls, compounding the effect of diminished secretion volume. In this study, we found serous cell hypotrophy/hypoplasia and dysfunction in VAD mice, which may contribute to the susceptibility to airway infection linked to VAD.
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